Annexin A2 Regulates Autophagy in Pseudomonas aeruginosa Infection through the Akt1-mTOR-ULK1/2 Signaling Pathway

J Immunol. 2015 Oct 15;195(8):3901-11. doi: 10.4049/jimmunol.1500967. Epub 2015 Sep 14.

Abstract

Earlier studies reported that a cell membrane protein, Annexin A2 (AnxA2), plays multiple roles in the development, invasion, and metastasis of cancer. Recent studies demonstrated that AnxA2 also functions in immunity against infection, but the underlying mechanism remains largely elusive. Using a mouse infection model, we reveal a crucial role for AnxA2 in host defense against Pseudomonas aeruginosa, as anxa2(-/-) mice manifested severe lung injury, systemic dissemination, and increased mortality compared with wild-type littermates. In addition, anxa2(-/-) mice exhibited elevated inflammatory cytokines (TNF-α, IL-6, IL-1β, and IFN-γ), decreased bacterial clearance by macrophages, and increased superoxide release in the lung. We further identified an unexpected molecular interaction between AnxA2 and Fam13A, which activated Rho GTPase. P. aeruginosa infection induced autophagosome formation by inhibiting Akt1 and mTOR. Our results indicate that AnxA2 regulates autophagy, thereby contributing to host immunity against bacteria through the Akt1-mTOR-ULK1/2 signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A2 / genetics
  • Annexin A2 / immunology*
  • Autophagy / genetics
  • Autophagy / immunology
  • Autophagy-Related Protein-1 Homolog
  • Cytokines / genetics
  • Cytokines / immunology
  • Female
  • Mice
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology*
  • Pseudomonas Infections / genetics
  • Pseudomonas Infections / immunology*
  • Pseudomonas aeruginosa / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology*

Substances

  • Annexin A2
  • Cytokines
  • mTOR protein, mouse
  • Ulk2 protein, mouse
  • Akt1 protein, mouse
  • Autophagy-Related Protein-1 Homolog
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Ulk1 protein, mouse